Compositions and methods for generating an immune response

Abstract

We have developed DNA and viral vectors that can be used, alone or in combination, as a vaccine against one HIV clade, subtype, or recombinant form of HIV or against multiple HIV clades, subtypes, or recombinant forms. Moreover, the vectors can encode a variety of antigens, which may be obtained from one clade or from two or more different clades, and the antigens selected and/or the manner in which the vectors are formulated (e.g., mixed) can be manipulated to generate a protective immune response against a variety of clades (e.g., the clades to which a patient is most likely to be exposed; with the proportions of the components of the vaccine tailored to the extent of the patient's risk to a particular clade or clades).

What is claimed is:  
     
       1. A vector comprising a insert encoding one or more antigens that elicit an immune response against an HIV of a subtype or recombinant form, said insert encoding for (a) a HIV-1 Gag protein in which both zinc fingers have been inactivated by amino acid changes corresponding to HIV Clade B HXB2 C392S, C395S, C413S and C416S; (b) a HIV-1 Pol protein in which (i) the integrase activity is inhibited by the deletion of integrase, (ii) the reverse transcriptase activity is inhibited by amino acid changes corresponding to HIV  Clade  B HXB2 D185N, W266T and E478Q, and (iii) the protease activity is inhibited by amino acid change corresponding to HIV Clade B HXB2D25A. 
     
     
       2. A vector comprising a insert encoding one or more antigens that elicit an immune response against an HIV of a subtype or recombinant form, said insert encoding for (a) a HIV Gag protein in which both zinc fingers have been inactivated by amino acid changes corresponding to HIV Clade B HXB2 C392S, C395S, C413S, and C416S; (b) a HIV-1 Pol protein in which (i) the integrase activity is inhibited by the deletion of integrase, (ii) the reverse transcriptase activity is inhibited by amino acid changes corresponding to HIV Clade B HXB2 D185N, W266T and E478Q, and (iii) the protease activity is inhibited by amino acid change corresponding to HIV Clade B HXB2 D25A; (c) a HIV-1 ADA Vpu protein comprising a mutant start codon by having a nucleic acid change G2C in the encoding sequence start site and having the nucleic acid sequence ATC at positions −5 to −3 upstream of the encoding start site. 
     
     
       3. The vector of  claim 1 , said insert having nucleic acid residues 106-6626 of SEQ ID NO:8. 
     
     
       4. The vector of  claim 2 , said insert having nucleic acid residues 106-6626 of SEQ ID NO: 9. 
     
     
       5. The vector of  claim 1 , said vector having nucleic acid residues 6627-9506 of SEQ ID NO:8. 
     
     
       6. The vector of  claim 1  having the nucleotide sequence of SEQ ID NO:8. 
     
     
       7. The vector of  claim 1  having the nucleotide sequence of SEQ ID NO:9. 
     
     
       8. A composition comprising a therapeutically effective amount of the vector of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       9. The composition of  claim 8  comprising an adjuvant selected from GM-CSF, IL-15 or IL-2. 
     
     
       10. The composition of  claim 8 , further comprising a second vector comprising a vaccine insert encoding one or more antigens that elicit an immune response against an HIV of a second subtype or recombinant form. 
     
     
       11. A method of eliciting a cellular and humoral immune response to an HIV antigen in a subject, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising the vector of  claim 1 . 
     
     
       12. The method of  claim 11  wherein administration of the composition produces virus-like particles (VLPs) when administered to the subject. 
     
     
       13. The method of  claim 11  wherein the composition comprises a second vector comprising an insert encoding one or more antigens that elicit an immune response against an HIV of a second subtype or recombinant form. 
     
     
       14. The method of  claim 13  wherein the composition comprises a third vector comprising an insert encoding one or more antigens that elicit an immune response against an HIV of a third subtype or recombinant form. 
     
     
       15. The method of  claim 13 , wherein administering the composition comprises administering a plasmid vector on more than one occasion for the purposes of priming or boosting a protective immune response. 
     
     
       16. The method of  claim 12 , wherein administering the composition comprises administering a plasmid vector on one or more than one occasion for the purpose of priming or boosting an immune response and administering a modified vaccinia Ankara on one or more than one subsequent occasion for the purpose of boosting or priming the immune response. 
     
     
       17. The method of  claim 15 , wherein the second vector insert is selected from the insert designated JS2, JS7, or JS7.1, and/or the insert designated IC2, IC25, IC48, or IC90, and/or the insert designated IN2 or IN3 and wherein the boosting comprises administering modified vaccinia Ankara vectors containing HIV sequences matched to the plasmids used for priming. 
     
     
       18. The method of  claim 15 , wherein the plasmid vector comprises an insert obtained from an HIV clade A and/or clade B, and/or clade C, and/or clade D, and/or clade E and/or clade F, and/or clade G and/or clade H and/or clade J, and/or clade K, and/or clade L and/or a recombinant subtype thereof and wherein the boosting comprises administering modified vaccinia Ankara vectors containing HIV sequences matched to the plasmids used for priming. 
     
     
       19. The method of  claim 12 , wherein administering the composition comprises administering modified vaccinia Ankara vectors on more than one occasion for the purposes of priming and boosting a protective immune response. 
     
     
       20. The method of  claim 15 , wherein the priming comprises administering clade B recombinant MVA and/or clade A recombinant MVA and/or clade C recombinant MVA and or any recombinant subtype thereof wherein the boosting comprises administering the same modified vaccinia Ankara vectors used for priming. 
     
     
       21. The method of  claim 15 , wherein the priming comprises administering clade A and/or clade B, and/or clade C, and/or clade D, and or/clade E and/or clade F, and/or clade G and/or clade H and/or clade J, and/or clade K, and/or clade L and/or any recombinant subtype thereof in a modified vaccinia Ankara vector and wherein the boosting comprises administering the same modified vaccinia Ankara vectors used for priming. 
     
     
       22. The method of  claim 15 , wherein the composition is administered by intradermal or intramuscular injection.